HIV and HCV infections are associated with an increased risk of osteoporotic fractures (OF). HIV/HCV co- infected subjects have a 3-fold increased fracture incidence compared to uninfected individuals, and 50% greater risk than HIV mono-infected. Despite being associated with this much higher fracture risk, HIV/HCV co- infection is not associated with lower bone mineral density (BMD) than HIV alone. The increased OF risk associated with HCV is likely mediated by micro-architectural changes that can be assessed using a novel technology called trabecular bone score (TBS) and possibly faster BMD decline. We have confirmed the existence of these HCV-associated micro-architectural changes in our preliminary studies and would now like to explore whether they underlie the increased fracture risk. Utilizing our ongoing cohort of 540 participants (57 HIV/HCV, 174 HIV, 131 HCV and 178 uninfected) we will evaluate longitudinal changes of BMD and TBS HIV and HCV patients. Validation of BMD and BMD changes on fracture risk in HIV and HCV populations has not been carried. Due to its deleterious effects on BMD, tenofovir disoproxil fumarate (TDF) is now largely being replaced in HIV therapy by the analog tenofovir alafenamide (TAF). The beneficial effects of this switch have also not been evaluated in a large cohort. Neither have the adherence and effectiveness of fracture preventive measures in HIV and HCV. Analyzing the use and effectiveness of these preventive measures and antiretroviral therapy changes will be the second aim of our study. To achieve this aim, we will utilize our prospective cohort and the much larger retrospective cohort of patients receiving care across the VA network, using a novel Natural Language Processing tool to extract anti-osteoporosis medication prescriptions, BMD and fracture data from the records. Finally, whether HCV-associated fracture risk is improved with HCV cure with interferon is doubtful based on recent evidence. The effects of current HCV therapy with Direct-Acting Antivirals (DAA) on OF risk has not been evaluated, and will constitute the third aim of our work. Our findings will have immediate therapeutic implications for Veterans: 1) understanding the mechanism(s) of increased fracture risk associated with HCV will allow targeted preventive and therapeutic interventions; 2) analyzing longitudinal changes in BMD and TBS in HIV and HCV will further elucidate mechanisms of increased fracture risk, and inform whether current monitoring guidelines are adequate; 3) determining whether HCV therapy with DAAs improves HCV-related increased fracture risk will inform whether additional measures should be taken to mitigate it; 4) determining whether the beneficial effect of antiretroviral switches on BMD seen in trials will be confirmed in improved fracture risk in a large clinical cohort will validate current trends in antiretroviral therapy; 5) evaluating the association of BMD and fracture risk in a large cohort of HIV and non-HIV and the use and effectiveness of fracture preventive measures will inform future policy decisions.